Method of making absorbable polymer blends of polylactides, polycaprolactone and polydioxanone

ABSTRACT

Absorbable binary and tertiary blends of homopolymers and copolymers of poly(lactide), poly(glycolide), poly(ε-caprolactone), and poly(p-dioxanone) are described. The blends when used to manufacture medical devices exhibit shape retention, dimensional stability and palpability without loss of the strength, stiffness and BSR found for poly(lactide) homopolyers and/or poly(lactide-co-glycolide) copolymers.

This is a division, of application Ser. No. 08/320,634, filed Oct. 11,1994, now U.S. Pat. No. 5,641,501 (issued Feb. 24, 1997)which is herebyincorporated by reference.

TECHNICAL FIELD

The field of art to which this invention relates is polymers, morespecifically, biocompatible, absorbable binary and tertiary polymerblends. Especially, blends of poly(lactide-co-glycolide) withpoly(ε-caprolactone) and poly(p-dioxanone) polymers.

BACKGROUND OF THE INVENTION

Polymers, including homopolymers and copolymers, which are bothbiocompatible and absorbable in vivo are well known in the art. Suchpolymers are typically used to manufacture medical devices which areimplanted in body tissue and absorb over time. Examples of such medicaldevices manufactured from these absorbable biocompatible polymersinclude suture anchors, sutures, staples, surgical tacks, clips, platesand screws, etc.

Absorbable, biocompatible polymers useful for manufacturing medicaldevices include both natural and synthetic polymers. Natural polymersinclude cat gut, cellulose derivatives, collagen, etc. Syntheticpolymers include aliphatic polyesters, polyanhydrides,poly(ortho)esters, and the like. Natural polymers typically absorb by anenzymatic degradation process in the body, while synthetic absorbablepolymers typically degrade by a hydrolytic mechanism.

Synthetic absorbable polymers which are typically used to manufacturemedical devices include homopolymers such as poly (glycolide),poly(lactide), poly (ε-caprolactone), poly(trimethylene carbonate) andpoly(p-dioxanone) and copolymers such as poly(lactide-co-glycolide),poly(ε-caprolactone-co-glycolide), and poly(glycolide-co-trimethylenecarbonate). The polymers may be statistically random copolymers,segmented copolymers, block copolymers, or graft copolymers. It is alsoknown that both homopolymers and copolymers can be used to prepareblends.

There is a constant need in this art for new polymer compositions havingimproved physical properties when molded or extruded into medicaldevices and further having excellent in vivo properties. For example, itis known that poly(lactide) and many copolymers of lactide and glycoliderich in lactide repeating units have superior in vivo properties.However, molded articles manufactured from these copolymers are known tohave poor dimensional stability due to a lack of crystallinity.

Additionally, for certain applications, such as plate and screw fixationdevices, it is necessary to be able to bend the device and then retainthe shape of the device to the contours of a body structure.

Furthermore, such devices should have excellent palpability. That is,the device, in vivo, should be able to soften and dissolve away slowlyupon absorption, rather than fragmenting into small granules which cancause tissue reaction.

Accordingly, what is needed in this art are novel polymer mixtures whichhave improved dimensional stability, shape retention, and palpability,while retaining the excellent strength, stiffness and breaking strengthretention (BSR) found in poly(lactide) homopolymers andpoly(lactide-co-glycolide) copolymers. Breaking strength retention is aconventionally known standard method of measuring the strength of adevice made of a bioabsorbable polymer as a function of time underbiological conditions in vitro or as a function of time after beingimplanted in vivo.

As described in U.S. Pat. Nos. 5,080,665 and 5,320,624 and Canadianapplications 2,079,274 and 2,079,275, various ductile, bioabsorbablepolymers (e.g., poly(ε-caprolactone), poly(trimethylene carbonate), andpoly(p-dioxanone)) have been blended with amorphous or low crystallinitypoly(lactide) hompolymers and poly(lactide-co-glycolide) copolymers toimprove device bendability at room temperature and their resistance tostress cracking. By the addition of these ductile polymers to the blend,the stiffness of the material decreases to a point where it is possibleto bend the device. Upon bending, crazes form, creating voids in thedevice which lead to permanent deformation. However, because of voidformation, local stress concentrations may form, which can often lead toan unsatisfactory decrease in stiffness, strength and BSR.

Therefore, to this end, it would be highly desirable to develop blendswhich were not dependent upon large additions of a ductile polymer tocreate bendability in the fixation device, but were dependent uponsmaller additions of a low melting polymer, in which the molded orextruded device when heated above the melting point of this low meltingpolymer could be bent or shaped to the contours of the fracture that isto be fixated. Once shaped, the device could be cooled to room or bodytemperature, recrystallizing the low melting polymer of the blend, andthereby, locking the newly formed shape of the device in place.

Additionally, since only small amounts of this low melting polymer orcopolymer would be incorporated into the blend, the excellent strength,stiffness and BSR of the major phase of the blend, poly(lactide)hompolymer or poly(lactide-co-glycolide) copolymer, would be retained.

DISCLOSURE OF THE INVENTION

Accordingly, a novel, absorbable, biocompatible, polymer blend isdisclosed. The polymer blend comprises a minor phase of about 0.1 weightpercent to about 9.9 weight percent of a mixture of homopolymers ofpoly(ε-caprolactone) and poly(p-dioxanone), or a blocky, segmented,statistically random, or branched copolymer of ε-caprolactone andp-dioxanone, with the remaining portion of the blend comprising a majorphase of poly(lactide) homopolymer and/or poly(lactide-co-glycolide)copolymer.

Yet another aspect of the present invention is a biomedical device,especially implantable wound closure devices such as suture anchors,surgical staples, clips, sutures, plates and screws, comprising theabove-described polymer blends.

Another aspect of the present invention is a medical device manufacturedfrom the above-described polymer blends of the present invention whichcan be heated above the melting point of the minor phase of the blend,then shaped to conform to a body structure, and then cooled to bodytemperature to retain the newly formed shape when implanted in vivo.

Still yet another aspect of the present invention is a method ofconforming a medical device to a body structure. The method entailsusing a medical device manufactured from the above-described polymerblends. Then, heating the device above the melting point of the minorphase of the blend, and shaping the device to conform to the shape ofthe body structure.

The foregoing and other features and advantages of the invention willbecome more apparent from the following description and accompanyingexamples.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph illustrating the in vitro BSR profiles of a blendcomposed of 95 weight percent of a 95:5 (mol/mol)poly(lactide-co-glycolide) copolymer and 5 weight percent of a 90:10(mol/mol) poly(ε-caprolactone-co-p-dioxanone) copolymer, and a 95:5(mol/mol) poly(lactide-co-glycolide) copolymer.

FIG. 2 is an illustration of a perspective view of a maxillofacial platewhich can be manufactured from the polymer blends of the presentinvention.

FIG. 3 is a perspective view of a test flex bar manufactured from apolymer blend of the present invention.

FIG. 4 is a perspective view of a test device used to test thebendability of the polymer blends of the present invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The aliphatic polyesters useful in the practice of the present inventionwill typically be synthesized by conventional techniques usingconventional processes. For example, in a ring opening polymerization,the aliphatic lactone monomers are polymerized in the presence of anorganometallic catalyst and an initiator at elevated temperatures. Theorganometallic catalyst is preferably tin based, e.g., stannous octoate,and is present in the monomer mixture at a molar ratio of monomer tocatalyst ranging from about 10,000/1 to about 100,000/1. The initiatoris typically an alkanol, a glycol, a hydroxyacid, or an amine, and ispresent in the monomer mixture at a molar ratio of monomer to initiatorranging from about 100/1 to about 5000/1. The polymerization istypically carried out at a temperature range from about 80° C. to about220° C., preferably from about 160° C. to about 200° C., until thedesired molecular weight and viscosity are achieved.

Under the above described conditions, the homopolymers and copolymerswill typically have a weight average molecular weight of about 10,000grams per mole to about 200,000 grams per mole, more typically about20,000 grams per mole to about 100,000 grams per mole, and mostpreferably about 40,000 grams per mole to about 70,000 grams per mole.Polymers of these molecular weight exhibit inherent viscosities betweenabout 0.1 to about 3.0 deciliters per gram (dL/g), more typically about0.2 to about 2.5 dL/g, and most preferably about 0.4 to about 2.0 dL/gas measured in a 0.1 g/dL solution of hexafluoroisopropanol (HFIP) at25° C.

Suitable aliphatic lactone monomers may be selected from the groupconsisting of glycolide, lactide (l, d, dl, meso), p-dioxanone,trimethylene carbonate, ε-caprolactone, delta-valerolactone,beta-butyrolactone, epsilon-decalactone, 2,5-diketomorpholine,pivalolactone, alpha, alphadiethylpropiolactone, ethylene carbonate,ethylene oxalate, 3-methyl-1,4-dioxane-2,5-dione,3,3-diethyl-1,4-dioxan-2,5-dione, gamma-butyrolactone,1,4-dioxepan-2-one, 1,5-dioxepan-2-one, 1,4-dioxan-2-one,6,8-dioxabicycloctane-7-one and combinations of two or more thereof.Preferred lactone monomers are selected from the group consisting ofglycolide, lactide, p-dioxanone, and ε-caprolactone.

Most preferably, the aliphatic polyesters consist ofpoly(ε-caprolactone), poly(p-dioxanone), and poly(lactide) homopolymers,and poly(ε-caprolactone-co-p-dioxanone) and poly(lactide-co-glycolide)copolymers.

The poly(lactide-co-glycolde) copolymers will contain sufficient amountsof glycolide repeating units to effectively provide faster bioabsorptionwhile still providing a reasonably long BSR profile. Thepoly(lactide-co-glycolide) copolymers will typically contain about 25mole percent to about 99 mole percent of lactide repeating units, andmore preferably about 50 mole percent to about 95 mole percent oflactide repeating units. The lower limit of lactide repeating units inthe copolymer is desirable because the presence of 50 mole percent ofglycolide repeating units provides faster bioabsorption to thecopolymer. The upper limit of lactide repeating units in the copolymeris desirable because it provides a long BSR profile to the copolymer.

The poly(ε-caprolactone-co-p-dioxanone) copolymers will containsufficient amounts of ε-caprolactone repeating units to effectivelyprovide acceptable bioabsorption and BSR profiles. Thepoly(ε-caprolactone-co-p-dioxanone) copolymers will preferably consistof about 5 mole percent to about 95 mole percent of ε-caprolactonerepeating units. Most preferably, thepoly(ε-caprolactone-co-p-dioxanone) copolymers will consist of about 50mole percent to about 95 mole percent of ε-caprolactone repeating units.The lower and upper limits of ε-caprolactone repeating units provide forcopolymers with a desirable range of BSR profiles, absorptions, andcrystallinity for bendability characteristics.

The polymer blends of the present invention are manufactured in aconventional manner, preferably in the following manner. Thehomopolymers and copolymers are individually charged into a conventionalmixing vessel having a conventional mixing device mounted therein suchas an impeller or equivalents thereof. Then, the polymers and copolymersare mixed at a temperature of about 150° C. to about 220° C., morepreferably from about 160° C. to about 200° C., for about 5 to about 90minutes, more preferably for about 10 to about 45 minutes, until auniformly dispersed polymer blend is obtained. Then, the polymer blendis further processed by removing it from the mixing device, cooling toroom temperature, grinding, and drying under pressures below atmosphericat elevated temperatures for a period of time using conventionalapparatuses and processes.

The binary polymer blends of the present invention will have sufficientamounts of poly(ε-caprolactone-co-p-dioxanone) copolymers to effectivelyimpart sufficient shapeability and palpability to the blend whileretaining the strength, stiffness, and BSR properties of thepoly(lactide) homopolymer and/or poly(lactide-co-glycolide) copolymers.The blends will typically contain about 0.1 weight percent to about 9.9weight percent of poly(ε-caprolactone-co-p-dioxanone) copolymer, andmost preferably about 0.5 weight percent to about 9.5 weight percent ofpoly(ε-caprolactone-co-p-dioxanone) copolymer. The major phase of theblend will comprise a poly(lactide) homopolymer and/orpoly(lactide-co-glycolide) copolymer of about 99.9 weight percent toabout 90.1 weight percent, and more preferably about 99.5 weight percentto about 90.5 weight percent.

The tertiary polymer blends of the present invention will containsufficient amounts of poly(ε-caprolactone) and poly(p-dioxanone)homopolymers to effectively impart shapeability and palpability to theblend while retaining the strength, stiffness and BSR properties of thepoly(lactide) homopolymer and/or poly(lactide-co-glycolide) copolymers.Furthermore, since it is known in the art that homopolymers more readilycrystallize than copolymers, the addition of poly(ε-caprolactone) andpoly(p-dioxanone) homopolymers has the additional ability to impartdimensional stability to the blends in comparison to those blends withpoly(ε-caprolactone-co-p-dioxanone) copolymers.

The tertiary polymer blends will contain a combination of about 0.1weight percent to about 9.9 weight percent of various amounts ofpoly(p-dioxanone) and poly(ε-caprolactone) homopolymers, and preferablyabout 0.5 weight percent to about 9.5 weight percent. The relativeproportion of caprolactone) homopolymer to poly(p-dioxanone) homopolymerin the blend will typically contain about 5 weight percent to about 95weight percent poly(ε-caprolactone), and preferably about 50 weightpercent to about 95 weight percent poly(ε-caprolactone) homopolymer. Themajor phase of the blend will comprise a poly(lactide) homopolymerand/or poly(lactide-co-glycolide) copolymers of about 99.9 weightpercent to about 90.1 weight percent, and more preferably about 99.5weight percent to about 90.5 weight percent.

It is well within the abilities of one skilled in the art to choosewhether to use a poly(lactide) homopolymer, a poly(lactide-co-glycolide)copolymer, or a combination thereof in the blends of the presentinvention. The skilled practitioner will base his choice, inter alia, onthe physical properties required of the blend, e.g., BSR.

Articles such as medical devices are molded from the polymer blends ofthe present invention by use of various conventional injection andextrusion molding equipment equipped with dry nitrogen atmosphericchamber(s) at temperatures ranging from about 160° C. to about 230° C.,more preferably from about 170° C. to about 220° C., with residencetimes of about 1 to about 10 minutes, more preferably from about 2 toabout 5 minutes.

The blends of this invention can be melt processed by numerousconventional methods and equivalents thereof to prepare a vast array ofuseful devices. These blends can be injection or compression molded tomake implantable medical and surgical devices, especially wound closuredevices. The preferred wound closure devices are surgical clips,staples, suture anchors, tacks, pins, plates and screws, and sutures.

Alternatively, the blends can be extruded to prepare fibers. Thefilaments thus produced may be fabricated into medical devices such assutures or ligatures, attached to surgical needles, packaged, andsterilized by known techniques. The blends of the present invention maybe spun as multifilament yarn and woven or knitted to form sponges orgauze, (or nonwoven sheets may be prepared) or used in conjunction withother molded compressive structures as prosthetic devices within thebody of a human or animal where it is desirable that the structure havehigh tensile strength and desirable levels of compliance and/orductility. Useful embodiments include medical devices such as tubes,including branched tubes, for artery, vein or intestinal repair, nervesplicing, tendon splicing, sheets for tying up and supporting damagedsurface abrasions, particularly major abrasions, or areas where the skinand underlying tissues are damaged or surgically removed.

Additionally, the blends can be molded to form films which, whensterilized, are useful as adhesion prevention barriers. Anotheralternative processing technique for the blends of this inventionincludes solvent casting, particularly for those applications where adrug delivery matrix is desired.

In more detail, the surgical and medical uses of the filaments, films,and molded articles of the present invention include, but are notnecessarily limited to:

Knitted medical devices, woven or non-woven, and molded medical devicesincluding:

a. burn dressings

b. hernia patches

c. medicated dressings

d. fascial substitutes

e. gauze, fabric, sheet, felt or sponge for liver hemostasis

f. gauze bandages

g. arterial graft or substitutes

h. bandages for skin surfaces

i. burn dressings

j. orthopedic pins, clamps, screws, and plates

k. clips

l. staples

m. hooks, buttons, and snaps

n. bone substitutes

o. needles

p. intrauterine devices

q. draining or testing tubes or capillaries

r. surgical instruments

s. vascular implants or supports

t. vertebral discs

u. extracorporeal tubing for kidney and heart-lung machines

v. artificial skin

w. stents

x. suture anchors and others.

Referring to FIG. 2, a specific medical device, a bone plate 10, isillustrated. Bone plate 10 can be manufactured from the polymer blendsof the present invention. The bone plate 10 is seen to have frame 20 anda plurality of openings 25 therethrough for receiving fasteners such asbone screws 45. Raised shoulders 27 extend from frame 20 and surroundeach opening 25. The bone plate 10 may be heated to a temperature offrom about 80° C. to about 120° C. in a conventional manner by, forexample, immersing the bone plate in a heated water bath, radiantheating, convective heating, etc., and combinations thereof. When heatedsufficiently, the plate 10 may be effectively shaped to conform to abody structure such as bone segment 40 by bending, twisting, etc., theframe 20. The plate 10 is then allowed to cool and the shaped plate 10is then applied next to the body structure using conventional surgicaltechniques. As seen in FIG. 2, the plate 10 has been slightly bowedprior to being affixed to a bone section 40. Plate 10 may be molded fromthe polymer blends of the present invention using conventional moldingapparatuses and conventional processes.

A test flex bar 50 manufactured from the polymer blends of the presentinvention is seen in FIG. 3. The rectangularly shaped flex bar 50 isseen to have elongated body section 60 having opposed ends 70. A testingdevice 100 for testing flex bars 50 is illustrated in FIG. 4. The devicehas a stationary frame 105 and a movable member 120 biased by helicalspring member 125. Moveable member 120 is seen to be mounted to shaftmember 107 which is free to slide through passage 109 in frame 105. Aflex bar 50 fits into frame 105 resting upon base member 130 havingsloping sides 132 and 134 which intersect at peak 136. The flex bar iscontacted by movable member 120. When the flex bar 50 is heated, e.g.,by hot water, the biased member 120 will cause flex bar 50 to bend aboutthe peak 136 of base member 130. Moveable member 120 is seen to havecavity 122 corresponding to the configuration of basemember 130.

EXAMPLES

The following examples are illustrative of the principles and practiceof this invention, although not limited thereto. Numerous additionalembodiments within the scope and spirit of the invention will becomeapparent to those skilled in the art. The examples describe new blendsof aliphatic polyesters, potentially useful as biomedical devices.

In the synthetic process, the high molecular weight aliphatic polyestersare prepared by a method consisting of reacting lactone monomers via aring opening polymerization at temperatures of 80° C. to 220° C., for 1to 24 hours under an inert nitrogen atmosphere until the desiredmolecular weight and viscosity are achieved.

In the blending process, the polymer blends of the present invention areprepared by individually charging the synthesized aliphatic homo- andco-polyesters into a conventional mixing vessel. The homopolymers andcopolymers are mixed at a temperature of 150° C. to 220° C., for 5 to 90minutes until a uniformly dispersed polymer blend is obtained.

In the examples, high molecular weight aliphatic polyesters and blendsthereof, are prepared and based upon lactone monomers such as glycolide,lactide, p-dioxanone, and ε-caprolactone.

In the examples which follow, the blends, polymers and monomers werecharacterized for chemical composition and purity (NMR, FT-IR), thermalanalysis (DSC), melt theology (melt stability and viscosity), molecularweight (inherent viscosity), and baseline and in vitro mechanicalproperties (Instron stress/strain).

FT-IR was performed on a Nicolet FT-IR. Polymer samples were meltpressed into thin films. Monomers were pressed into KBr pellets. ¹ H NMRwas performed on a 300 MHz NMR using CDCl₃ or HFAD as a reference.

Thermal analysis of blends, polymers and monomers was performed on aDupont 912 Differential Scanning Calorimeter (DSC) at a heating rate of10° C./min. A Fisher-Johns melting point apparatus was also utilized todetermine melting points of monomers. Thermal gravimetric analysis wasperformed on a Dupont 951 TGA at a rate of 10° C./min. under a nitrogenatmosphere. Isothermal melt stability of the polymers was alsodetermined by a Rheometrics Dynamic Analyzer RDA II for a period of 1hour at temperatures ranging from 160° C. to 230° C. under a nitrogenatmosphere.

Inherent viscosities (I.V., dL/g) of the blends and polymers weremeasured using a 50 bore Cannon-Ubbolhode dilution viscometer immersedin a thermostatically controlled water bath at 25° C. utilizingchloroform or HFIP as the solvent at a concentration of 0.1 dL/g.

Melt viscosity was determined utilizing a Rheometrics Dynamic AnalyzerRDA II at temperatures ranging from 16° C. to 230° C. at rate of 1°C./min. to 10° C./min. at frequencies of 1s⁻¹ to 100s⁻¹ under a nitrogenatmosphere.

Baseline and in vitro mechanical properties of cylindrical dumbbells ofthe blends were performed on an Instron model 1122 at a crosshead rateof 0.35 in/min. Specimen gauge length was 0.35 in., with a width of 0.06in. Results are an average of 8 to 12 dumbbell specimens.

The cylindrical dumbbells were prepared by utilizing a CSI Mini-maxinjection molder equipped with a dry nitrogen atmospheric chamber attemperatures ranging from 170° C. to 220° C. with a residence time of 3minutes.

In vitro studies were determined in a phosphate buffer solution(pH=7.27) at a temperature of 37° C. for periods of 1, 3, and 6 weeks.Cylindrical dumbbells (8 to 10 of a total weight of 2.4 to 3.0 grams)were placed in 100 ml of buffer solution.

Several synthetic and blending examples will be described in thefollowing few pages. Parts and percentages where used are parts andpercentages as specified as weight or moles.

Example 1

Synthesis of a 95:5 (tool/tool) poly(lactide-co-glycolide) copolymer

The method described below and utilized in this example is similar tothose described in U.S. Pat. Nos. 4,643,191, 4,653,497, 5,007,923,5,047,048 which are incorporated by reference, and is known to thoseskilled in the art.

To a flame dried 500 mL 1-neck round bottom flask equipped with anoverhead mechanical stirrer and nitrogen inlet, 300 grams (2.08 moles)of L(-) lactide, 12.8 grams (0.110 moles) of glycolide, 0.53 grams(7×10⁻³ moles) of glycolic acid initiator, and 131 microliters of a0.33M solution of stannous octcate catalyst were added.

The assembly was then placed in a high temperature oil bath at 185° C.The stirred monomers quickly began to melt. The low viscosity meltquickly increased in viscosity. Mechanical stirring of the highviscosity melt was continued for a total reaction time of 4 hours.

The 95:5 (mol/mol) poly(lactide-co-glycolide) copolymer was removed fromthe bath, cooled to room temperature under a stream of nitrogen,isolated and ground. The polymer was then dried under vacuum at 110° C.for 24 hours. Inherent viscosity using HFIP as a solvent was 1.95 dL/g.

Example 2

Synthesis of a 90:10 (mol/mol) poly(ε-caprolaptone-co-p-dioxanone)copolymer

The method described below in this example is similar to those describedin U.S. Pat. Nos. 4,643,191, 4,653,497, 5,007,923, 5,047,048 which areincorporated by reference, and is known to those skilled in the art.

To a flame dried 500 mL 1-neck round bottom flask equipped with anoverhead mechanical stirrer and nitrogen inlet, 251.13 grams (2.2 moles)of ε-caprolactone, 22.5 grams (0.22 moles) of p-dioxanone, 0.84 grams(0.011 moles) of glycolic acid initiator, and 147 microliters of a 0.33Msolution of stannous octcate catalyst were added.

The assembly was then placed in a high temperature oil bath at 190° C.The stirred monomers quickly began to melt. The low viscosity meltquickly increased in viscosity. Mechanical stirring of the highviscosity melt was continued for a total reaction time of 24 hours.

The 90:10 (mol/mol) poly(ε-caprolactone-co-p-dioxanone) copolymer wasremoved from the bath, cooled to room temperature under a stream ofnitrogen, isolated and ground. The polymer was then dried under vacuumat 40° C. for 24 hours. Inherent viscosity using HFIP as a solvent was1.17 dL/g.

Example 3

Blending of a 95:5 (mol/mol) poly(lactide-co-glycolide) copolymer with a90:10 (mol/mol) poly(ε-caprolactone-co-p-dioxanone) copolymer at ablended weight ratio of 95:5

29.45 grams of a 95:5 (mol/mol) poly(lactide-co-glycolide) prepared asdescribed in Example 1 was melt blended with 1.55 grams of the 90:10(mol/mol) poly(ε-caprolactone-co-p-dioxanone) copolymer of Example 2 ata weight ratio of 95:5 in a Brabender Plasti-corder mixer at atemperature of 170° C. for 23 minutes. The resulting blend was removedfrom the Brabender mixer, cooled, ground and dried under vacuum at 50°C. for 24 hours. Inherent viscosity using HFIP as a solvent was 1.90dL/g.

Example 4

Blending of a 95:5 (mol/mol) poly(lactide-co-glycolide) copolymer with a90:10 (mol/mol) poly(ε-caprolactone-co-p-dioxanone) copolymer at ablended weight ratio of 99.5:0.5

30.845 grams of the 95:5 (mol/mol) poly(lactide-co-glycolide) copolymeris prepared in accordance with the procedure of Example 1 and is meltblended with 0.155 grams of a 90:10 (mol/mol)poly(ε-caprolactone-co-p-dioxanone) copolymer prepared in accordancewith Example 2 at a weight ratio of 99.5:0.5 prepared in accordance withExample 3 in a Brabender Plasti-corder mixer at a temperature of 170° C.for 23 minutes. The blend is removed from the Brabender mixer, cooled,ground and dried under vacuum at 50° C. for 24 hours.

Example 5

Blending of a 95:5 (mol/mol) poly(lactide-co-glycolide) copolymer with a90:10 poly(ε-caprolactone-co-p-dioxanone) copolymer at a blended weightratio of 90.5:9.5

28.055 grams of a 95:5 (mol/mol) poly(lactide-co-glycolide) copolymer isprepared in accordance with the procedure of Example 1 and is meltblended with 2.945 grams of a 90:10 poly(ε-caprolactone-co-p-dioxanone)copolymer prepared in accordance with Example 2 at a weight ratio of90.5:9.5 prepared in accordance with Example 3 in a BrabenderPlasticorder mixer at a temperature of 170° C. for 23 minutes. The blendis removed from the Brabender mixer, cooled, ground and dried undervacuum at 50° C. for 24 hours.

Example 6

Blending of a 95:5 (mol/mol) poly(lactide-co-glycolide) copolymer withpoly(ε-caprolactone) and poly(p-dioxanone) homopolymers at a blendedweight ratio of 90.5:4.5:5.0

28.055 grams of a 95:5 (mol/mol) poly(lactide-co-glycolide) copolymerprepared as described in Example 1 was melt blended with 1.395 grams ofpoly(ε-caprolactone) and 1.55 grams of poly(p-dioxanone) homopolymers,as prepared and described in U.S. Pat. Nos. 4,643,191, 4,653,497,5,007,923, 5,047,048 which are incorporated by reference, and are knownto those skilled in the art, at a weight ratio of 90.5:4.5:5.0 in aBrabender Plasti-corder mixer at a temperature of 170° C. for 23minutes. The blend was removed from the Brabender mixer, cooled, groundand dried under vacuum at 50° C. for 24 hours. Inherent viscosity usingHFIP as a solvent was 1.84 dL/g.

Example 7

Blending of a 95:5 (mol/mol) poly(lactide-co-glycolide) copolymer withpoly(ε-caprolactone) and poly(p-dioxanone) homopolymers at a blendedweight ratio of 99.5:0.25:0.25

30.845 grams of a 95:5 (mol/mol) poly(lactide-co-glycolide) copolymer isprepared in accordance with the procedure of Example 1 and is meltblended with 0.775 grams each of poly(ε-caprolactone) andpoly(p-dioxanone) homopolymers, prepared in accordance with theprocedures disclosed in U.S. Pat. Nos. 4,643,191, 4,653,497, 5,007,923,5,047,048 which are incorporated by reference, and are known to thoseskilled in the art, at a weight ratio of 99.5:0.25:0.25 prepared inaccordance with Example 3 in a Brabender Plasticorder mixer at atemperature of 170° C. for 23 minutes. The blend is removed from theBrabender mixer, cooled, ground and dried under vacuum at 50° C. for 24hours.

Example 8

Flex bar bending experiments on blends of poly(lactide-co-glycolide),poly(ε-caprolactone) and poly(p-dioxanone)

Flex bars 50 of the blends of Examples 3 and 6, 2 inches×0.375 inches×60mils thick, used for shapeability testing (See FIG. 3), were prepared bycompression molding utilizing a Carver Model 2696 Hydraulic Press attemperatures ranging from 150° C. to 220° C. for 10 minutes at pressuresof 1,000 to 5,000 psi. Once formed, the flex bars 50 were slowly cooledto room temperature under pressure.

For bendability or shapeability testing, the flex bars 50 were placed ina bending testing device 100 as illustrated in FIG. 4. The bendingdevice was then placed in a hot water bath (80°-100° C.), and the flexbar was bent to a 45° angle. Five flex bars 50 of each of the blendswere then placed in vitro in a phosphate buffer solution (pH=7.27) at atemperature of 37° C. for periods of 1, 3, and 6 weeks. The change inthe angle of the flex bars 50 from the horizontal was then measured. Theresults are shown in Table 1.

                                      TABLE 1                                     __________________________________________________________________________    BASELINE AND IN-VITRO SHAPEABILITY OF MELT BLENDS                                                      Baseline (0-day)                                                                      In-Vitro Wk 1                                                                           In-Vitro Wk 3                                                                           In-Vitro Wk 6                                     Angle of bend                                                                         Angle of bend                                                                        %  Angle of bend                                                                        %  Angle of                                                                             %end              Blend Type                                                                            Wt. %                                                                             Composition  (degrees)                                                                             (degrees)                                                                            Loss                                                                             (degrees)                                                                            Loss                                                                             (degrees)                                                                            Loss              __________________________________________________________________________    Binary Blends                                                                         95/5                                                                              (L/G 95/5) - (PCL/PDS 90/10)                                                               45      45     0  45     0  45     0                 Tertiary Blends                                                                       95/5/5                                                                            (L/G 95/5) - (PDS) - (PCL)                                                                 45      45     0  45     0  45     0                 __________________________________________________________________________

Example 9

A patient having a fractured femur is prepared for surgery usingconventional surgical techniques. The patient's femur is exposed usingconventional surgical techniques so that the bone fracture site 40 isexposed as seen in FIG. 2. The surgeon takes a bone plate 10manufactured from the polymer and copolymer blends of the presentinvention and immerses it in a vessel containing sufficiently warm watere.g., 80°-100° C. for a sufficient amount of time to effectively softenthe plate 10. The plate 10 is removed from the vessel and the surgeonshapes the bone plate 10 by bending it and then allows it to cool for asufficient amount of time so that it effectively retains its shape. Theplate 10 is then mounted to fracture site 40 in a conventional mannerusing conventional biocompatible bone screws 45. The patient's thigh isthen closed using conventional surgical techniques.

The polymer blends of the present invention have many advantages overthe polymer blends of the prior art. For example, in the development ofa maxillofacial fixation device one of the concerns involves the abilityof the device to be shaped by the surgeon during surgery to the contoursof, for example, a fractured bone 40 as seen in FIG. 2. Once contouredto the fractured bone, the device must retain its shape. That is, thepolymer must have shape retention characteristics.

For example, as found for the binary blends of this invention, by theaddition of small amounts of a poly(ε-caprolactone-co-p-dioxanone)copolymer to a poly(lactide-co-glycolide) copolymer, better shaperetention can be obtained. That is, by heating the plate to 80°-120° C.to bend it to the shape of the fractured bone, thepoly(ε-caprolactone-co-p-dioxanone) copolymer will melt, causing theplate to "flow" and bend more easily. Once the plate has cooled, thepoly(ε-caprolactone-co-p-dioxanone) copolymer crystallizes, "locking"the newly contoured shape into the plate.

That is, when flex bars 50 of the present invention (FIG. 3) are bent atelevated temperatures (80°-12° C.) by a mechanical assist device 100(FIG. 4) to a 45 degree angle, then held at this position until cooledto room or body temperature, virtually no change in angular shape of theflex bar occurs over 6 weeks in vitro at 37° C. (buffer solution,pH=7.27) (See Table 2).

                                      TABLE 2                                     __________________________________________________________________________    BASELINE AND IN-VITRO BSR TENSILE STRENGTH OF MELT BLENDS                                              Baseline (0-day)                                                                      In-Vitro BSR Wk 1                                                                       In-Vitro BSR Wk                                                                         In-Vitro BSR Wk 6                                 Yield Strength                                                                        Yield Strength                                                                       %  Yield Strength                                                                       %  Yield                                                                                %trength          Blend Type                                                                            Wt. %                                                                             Composition  psi     psi    Loss                                                                             psi    Loss                                                                             psi    Loss              __________________________________________________________________________    Binary Blends                                                                         95/5                                                                              (L/G 95/5) - (PCL/PDS 90/10)                                                               9800    8200   16 6600   32 4900   50                Tertiary Blends                                                                       95/5/5                                                                            (L/G 95/5) - (PDS) - (PCL)                                                                 7900    5500   31 4800   39 3200   60                __________________________________________________________________________

This data strongly indicates that shapeability in a device can beobtained by utilizing small amounts of semi-crystalline,poly(ε-caprolactone-co-p-dioxanone) copolymers or poly(ε-caprolactone)and poly(p-dioxanone) homopolymers a blend with poly(lactide)homopolymers and/or poly(lactide-co-glycolide) copolymers.

These results are in direct contrast to the previous art which describesthat the addition of a large amount of a ductile polymer topoly(lactide) homopolymers and/or poly(lactide-co-glycolide) copolymersis necessary to allow the device to be bent to the contours of thefractured bone. That is, the bendability or shapeability occurs througha lowering of the stiffness of the blend. This allows the surgeon tobend the device, causing crazes to form, resulting in permanentdeformation of the device.

However, due to the addition of a large amount of ductile polymer tothese blends, the blends of the previous art can lose a great deal ofstrength, stiffness and BSR. Since high strength, stiffness and a longBSR profile are required for correct fracture fixation, the loss of suchproperties is detrimental to the development of devices for plastic andreconstructive, and orthopedic surgical applications.

Lower strength, stiffness and BSR will not occur for the blends of thepresent invention, since only small amounts of semi-crystalline polymersare added. For example, as shown in Table 2 and FIG. 1, virtually nodifference is observed in the BSR profiles of a 95:5 (mol/mol)poly(lactide-co-glycolide) copolymer, and a blend of a 95:5 (mol/mol)poly(lactide-co-glycolide) copolymer and a 90:10poly(ε-caprolactone-co-p-dioxanone) copolymer at a blend ratio of 95/5weight percent.

These results are a strong indication that small additions of thesesemi-crystalline polymers to poly(lactide) homopolymers and/orpoly(lactide-co-glycolide) copolymers does not limit their physicalproperties.

Additionally, these blends will have improved palpability. Sincepoly(ε-caprolactone-co-p-dioxanone) copolymers can surface erode, thedevice will slowly dissolve away rather than fragmenting into smallgranules. Formation of small granules of polymer can lead to tissuereaction.

Therefore, binary blends consisting of a poly(lactide) homopolymersand/or poly(lactide-co-glycolide) copolymers withpoly(ε-caprolactone-co-p-dioxanone) copolymers will give desirableproperties such as shape retention and palpability while maintaining thehigh strength, stiffness and BSR of the poly(lactide) homopolymersand/or poly(lactide-co-glycolide) copolymers.

Furthermore, tertiary blends of poly(lactide) homopolymers and/orpoly(lactide-co-glycolide) copolymers with poly(ε-caprolactone) andpoly(p-dioxanone) homopolymers will also impart the desirable propertiesof shape retention and palpability while maintaining the high strength,stiffness and BSR of the poly(lactide) homopolymers and/orpoly(lactide-co-glycolide) copolymers. In addition, since it is wellknown that homopolymers more readily crystallize than copolymers, thetertiary blends will have improved dimensional stability in comparisonto the binary blends.

Medical devices made from the polymer blends of the present inventionare typically pre-packaged by the manufacturer using conventionalpackages and packaging materials. The devices in the packages are thentypically sterilized by the manufacturer using conventionalsterilization processes and procedures, including ethylene oxide,radiation, heat, etc. Although not desirable, the medical devices of thepresent invention can be sterilized at the point of use, e.g., thehospital, but only if the devices have not been previously sterilized.

Although this invention has been shown and described with respect todetailed embodiments thereof, it will be understood by those skilled inthe art that various changes in form and detail thereof may be madewithout departing from the spirit and scope of the claimed invention.

We claim:
 1. A method of conforming the shape of a bioabsorbable medicaldevice to a body structure comprising the steps of:heating abioabsorbable medical device sufficiently to effectively allow themedical device to be formed; conforming the heated medical device to ashape of a body structure; cooling the medical device sufficiently sothat the device effectively retains the shape, wherein the medicaldevice comprises a bioabsorbable polymer blend which comprises: a majorphase comprising about 90.1 weight percent to about 99.9 weight percentof a polymer selected from the group consisting of poly(lactide)homopolymers and poly(lactide-co-glycolide) copolymers, and combinationsthereof; and, a minor phase comprising about 0.1 weight percent to about9.9 weight percent of a mixture of poly(ε-caprolactone) andpoly(p-dioxanone) homopolymers, wherein said blend has a weight fractionof the major phase and minor phase equal to 100.0 weight percent.
 2. Amethod of conforming the shape of a bioabsorbable medical device to abody structure comprising the steps of:heating a bioabsorbable medicaldevice sufficiently to effectively allow the medical device to beformed; conforming the heated medical device to a shape of a bodystructure; cooling the medical device sufficiently so that the deviceeffectively retains the shape, wherein the medical device comprises abioabsorbable polymer blend which comprises: a major phase comprisingabout 90.1 weight percent to about 99.9 weight percent of a polymerselected from the group consisting of poly(lactide) homopolymers andpoly(lactide-co-glycolide) copolymers, and combinations thereof; and, aminor phase comprising about 0.1 weight percent to about 9.9 weightpercent of a copolymer of poly(ε-caprolactone-co-p-dioxanone), whereinsaid blend has a weight fraction of the major phase and minor phaseequal to 100.0 weight percent.